Rewarding effects of addictive drugs become associated with cues that subsequently trigger relapse. Animal models of reinstatement combine neurobiological and behavioral approaches that advance understanding and treatment of addiction. In some models of cue-induced relapse, a discriminative stimulus (SD) is used during conditioning, whereby the SD sets the occasion for an instrumental response (lever pressing). Other models utilize a conditioned stimulus (CS), whereby the lever press initiates the CS and drug infusion. After conditioning and withdrawal, a CS can function as a conditioned reinforcer when presented contingent upon responding, i.e., after the lever press. But random presentations of the CS (non-contingently) fail to reinstate responding. In contrast, non-contingent presentations of SDs reliably reinstate drug seeking (relapse). It is important to determine whether brain areas involved in addiction and relapse process the CS differently from the SD. Therefore, an audible tone will be conditioned as a CS (CS+) in one group and as a SD (S+) in another group of rats self-administering cocaine. Responding to a tone of a different frequency (CS- or S-, respectively) will be measured on interdigitated days on which cocaine is not available, to establish stimulus discrimination. After two weeks' abstinence, the tones will be presented in tests of reinstatement (without infusions). We will record single neuron activity in the accumbens core and shell subregions and their targets in ventral pallidum (VPdl and VPvm, respectively) during these cued reinstatement tests. In half the CS group, the CS+ tone will be presented contingently, after the instrumental response (lever press), to verify its ability to function as a conditioned reinforcer; given that core circuitry has been implicated in conditioned reinforcement and has somatomotor connections, it is predicted that core and VPdl neurons will show significant phasic activity related to the lever press during responding maintained by the conditioned reinforcer. In the SD group and the other half of the CS group, the tone will be presented non-contingently; it is predicted that 1) the S+ will but the CS+ will not increase lever pressing, and 2) shell/VPvm neurons, which mediate the ability of Pavlovian stimuli to activate instrumental responses, in the SD group will be more responsive to the S+ than those in the CS group to the CS+. Findings will help clarify neurobiological mechanisms of cue-induced relapse to drug seeking, toward developing more effective treatment strategies. [unreadable] [unreadable] [unreadable]